甲酰肽受体1（Formyl peptide receptor 1, FPR1）属于A族G蛋白偶联受体，可被菌源性甲酰化肽及部分病毒来源的蛋白所激活，引起嗜中性粒细胞趋化、脱颗粒和超氧离子释放。活化FPR1有助于清除病原菌和损伤组织，在先天性免疫反应中发挥重要的作用。
中国科学院上海药物研究所/国家新药筛选中心、复旦大学和上海交通大学的科研人员对该受体开展了药物基因组学研究，通过检测209名汉族人群FPR1基因的单核苷酸多态性（Single nucleotide polymorphisms, SNP）构建了相应的单倍型，发现有5个SNP位点的等位基因频率与其他人种存在显著差异。据此，他们把呈现汉族人群中主要单倍型的FPR1基因在CHO-Gα16细胞中表达，应用该受体的选择性激动剂（fNle-Leu-Phe-Nle-Tyr-Lys-fluorescein）评估各单倍型与环孢菌素的亲和力。研究表明，环孢菌素对带有V101L多态性位点的FPR1之亲和力及其功能的抑制效应明显高于表型为V101的受体。这一结果提示带有FPR1基因V101L多态性位点的病人在长期接受环孢菌素A治疗时，有可能会因FPR1受体功能被过度抑制而产生未曾关注过的毒副作用。
由王明伟教授领衔实施的这项研究历时4年，得到国家重大科技专项的资助，相关成果2月4日在著名学刊Biochemical Journal上在线发表（http://www.biochemj.org/bj/imps/abs/BJ20121839.htm）。该杂志的编辑认为“该论文从药物基因组学的探索中产生假说，并随之在具体的实验中进行验证，是开展转化医学研究的一个很好范例”。（生物谷Bioon.com）
doi:10.1042/BJ20121839
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V101L of human formyl peptide receptor 1 (FPR1) increases the receptor affinity and augments the antagonism mediated by cyclosporins
Caihong Zhou, Yan Zhou, Jia Wang, Yang Feng, Haonan Wang, Jinglun Xue, Yani Chen, Richard D. Ye and Ming-Wei Wang
Genetic variation plays a major role in drug response variability. Cyclosporin A (CsA), a widely used immunosuppressive agent, is a specific antagonist for formyl peptide receptor 1 (FPR1), which is an important G protein-coupled chemoattractant receptor in the innate immune system. In order to study the variable responses of cyclosporins to different FPR1 mutants, we investigated the distribution of human FPR1 haplotypes among 209 healthy Han Chinese subjects. The haplotype pattern in Han Chinese were characterized based on five single nucleotide polymorphisms (SNPs), including rs5030878 (p.T11I), rs2070745 (p.V101L), rs5030880 (p.R190W), rs1042229 (p.N192K) and rs867228 (p.A346E). Receptor binding affinity of cyclosporins to FPR1 haplotypes was assessed using fNle-Leu-Phe-Nle-Tyr-Lys-fluorescein in CHO-Gα16 cells stably transfected with cDNAs encoding the top 12 FPR1 haplotypes in Han Chinese. Variants of FPR1 carrying a single amino acid substitution of leucine for valine at position 101 (p.L101) displayed significantly higher pKi values for CsA and CsH, indicative of an improved receptor affinity. The polymorphism of FPR1 p.L101 also enhanced the inhibitory effects of cyclosporins on fMLF-induced activities including calcium mobilization, cell chemotaxis and MAPK phosphorylation. These results point to a possible complication for clinical use of CsA in patients carrying the p.L101 allele of FPR1.
